Effects of intranasal hypocretin-1 (orexin A) on sleep in narcolepsy with cataplexy.

BACKGROUND: The neuropeptides hypocretin-1 and -2 (hcrt-1 and -2, also known as orexin A and B) are crucially involved in the regulation of sleep/wake states. On the one hand, the sleep-wake disorder narcolepsy can be caused by an hcrt-1 deficiency. On the other, intracerebral administration of hcrt-1 produces an increase in wakefulness at the expense of REM sleep in normal and narcoleptic animals. In humans intranasal administration has been shown to effectively deliver neuropeptides directly to the central nervous system. We hypothesised that the intranasal application of hcrt-1 increases wakefulness and reduces REM sleep in the natural human hcrt-1 deficiency narcolepsy with cataplexy. METHODS: In this double-blind, random-order crossover, placebo-controlled, within-subject design study we administered human recombinant hcrt-1 (435 nmol) intranasally to eight subjects with narcolepsy with cataplexy before night sleep, followed by standard polysomnography. RESULTS: Although intranasal administration of hcrt-1 had no statistically significant effect on nocturnal wakefulness, we found that it reduced REM sleep quantity, particularly during the second half of the recording. Furthermore, intranasal hcrt-1 had a clear REM sleep stabilising effect and led to significantly reduced direct wake to REM transitions. CONCLUSION: In this pilot study we found, first, evidence that the intranasal administration of hcrt-1 has functional effects on sleep in narcolepsy with cataplexy. Our results may encourage the use of the intranasal approach in further studies on hypocretinergic sleep regulation and might also contribute to the future development of a causal treatment for narcolepsy with cataplexy.

Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia.

Neurodevelopmental abnormalities together with neurodegenerative processes contribute to schizophrenia, an etiologically heterogeneous, complex disease phenotype that has been difficult to model in animals. The neurodegenerative component of schizophrenia is best documented by magnetic resonance imaging (MRI), demonstrating progressive cortical gray matter loss over time. No treatment exists to counteract this slowly proceeding atrophy. The hematopoietic growth factor erythropoietin (EPO) is neuroprotective in animals. Here, we show by voxel-based morphometry in 32 human subjects in a placebo-controlled study that weekly high-dose EPO for as little as 3 months halts the progressive atrophy in brain areas typically affected in schizophrenia, including hippocampus, amygdala, nucleus accumbens, and several neocortical areas. Specifically, gray matter protection is highly associated with improvement in attention and memory functions. These findings suggest that a neuroprotective strategy is effective against common pathophysiological features of schizophrenic patients, and strongly encourage follow-up studies to optimize EPO treatment dose and duration.

Effects of olanzapine on slow wave sleep, sleep spindles and sleep-related memory consolidation in schizophrenia.

INTRODUCTION: Memory deficits and sleep disturbances are common clinical features of schizophrenia. Sleep is supposed to promote memory consolidation and the antipsychotic olanzapine is suggested to improve both sleep and memory functions. Therefore we performed a study to analyse the acute effects of olanzapine on distinct sleep parameters and sleep-related memory consolidation in parallel. METHODS: We studied 26 patients with schizophrenia on stable antipsychotic medication with amisulpride (age range 19-44 years). Immediately before polysomnography and the morning after we performed neuropsychological tasks. Before the third night in the sleep laboratory, patients received either olanzapine or a placebo. RESULTS: We found a significant positive association for slow wave sleep and declarative memory performance in schizophrenia at baseline. Additionally, Stage 2 sleep spindle density was positively related to overnight memory consolidation. Olanzapine caused a significant increase in the amount of slow wave sleep in accordance with recent studies, but led also to a significant decrease in sleep spindle density, which had not been described before. Memory performance the next morning was not different between the two groups. DISCUSSION: Since not only slow wave sleep but also sleep spindles are supposed to promote sleep-related memory consolidation, we suggest that a putative positive effect on memory performance by slow wave sleep augmentation is neutralised by the decrease in sleep spindles due to olanzapine.

Improvement of cognitive functions in chronic schizophrenic patients by recombinant human erythropoietin.

Schizophrenia is increasingly recognized as a neurodevelopmental disease with an additional degenerative component, comprising cognitive decline and loss of cortical gray matter. We hypothesized that a neuroprotective/neurotrophic add-on strategy, recombinant human erythropoietin (rhEPO) in addition to stable antipsychotic medication, may be able to improve cognitive function even in chronic schizophrenic patients. Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter, proof-of-principle (phase II) study. This study had a total duration of 2 years and an individual duration of 12 weeks with an additional safety visit at 16 weeks. Chronic schizophrenic men (N=39) with defined cognitive deficit (>or=1 s.d. below normal in the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)), stable medication and disease state, were treated for 3 months with a weekly short (15 min) intravenous infusion of 40,000 IU rhEPO (N=20) or placebo (N=19). Main outcome measure was schizophrenia-relevant cognitive function at week 12. The neuropsychological test set (RBANS subtests delayed memory, language-semantic fluency, attention and Wisconsin Card Sorting Test (WCST-64) - perseverative errors) was applied over 2 days at baseline, 2 weeks, 4 weeks and 12 weeks of study participation. Both placebo and rhEPO patients improved in all evaluated categories. Patients receiving rhEPO showed a significant improvement over placebo patients in schizophrenia-related cognitive performance (RBANS subtests, WCST-64), but no effects on psychopathology or social functioning. Also, a significant decline in serum levels of S100B, a glial damage marker, occurred upon rhEPO. The fact that rhEPO is the first compound to exert a selective and lasting beneficial effect on cognition should encourage new treatment strategies for schizophrenia.

[Current standing of forensic psychotherapy in Germany]. / Zum gegenwärtigen Stand der Forensischen Psychotherapie in Deutschland.

Although treatment of inmates already has got a long tradition in Germany, forensic psychotherapy is - especially outside the so-called German "Massregelvollzug" - only at its beginnings, and consistent theories about delinquency and treatment programmes have not yet been established. While international studies show high prevalence of mental disorders in prisons (up to 60 - 70 %), in Germany even basic epidemiological data about the prevalence of mental disorders among inmates is still missing. Thus, the need for psychotherapy can only be roughly estimated. Ethical implications regarding the self-image, an ambivalent assignment for treatment (given by society) and a recent tightening of German law create a difficult framework for forensic psychotherapy, complicating the establishment as well as the evaluation of new treatment programmes, especially since many people still doubt the efficiency of forensic psychotherapy for delinquents despite convincing counter-evidence. It seems obvious that in Germany much research has to be done in the fields of epidemiology as well as in forensic psychotherapy in order to gain basic data and to be then able to provide effective psychotherapeutic treatment facilities aiming at the needs of mentally disturbed offenders.

[Zolpidem: the risk of tolerance and dependence according to case reports, systematic studies and recent molecularbiological data]. / Zolpidem: Zur Entwicklung von Toleranz und Abhängigkeit anhand von Fallberichten, systematischen Studien und aktuellen molekularbiologischen Daten.

Our group as well as about 20 other publications report cases of dependence from zolpidem. Furthermore, there is epidemiological and polysomnographic evidence that there is a risk for tolerance and dependence for zolpidem although lower than in the case of benzodiazepines. Recent molecularbiological findings offer interesting data in this respect. Whereas in the recommended dose range zolpidem almost exclusively binds to the alpha(1) subunit of the GABA(A) receptor associated with sleep promotion, in higher doses it also binds the alpha(2), alpha(3) and alpha(5) subunits typically targeted by benzodiazepines and associated with anxiolytic effects. Moreover, because age, gender and alcohol were shown to significantly affect expression of these subunits in individual brain regions, dosage and duration of treatment with zolpidem as well as age, gender and additional consumption of alcohol, a history of abuse and dependence might play a role in the development of tolerance and dependence in individual patients.

Reduced olfactory performance in patients with major depression.

The aim of the present study is to investigate olfactory sensitivity and odor evaluations in a homogeneous sample of unipolar depressive patients using pure olfactory odors. Twenty-four in-patients with major depressive disorder (MDD) were investigated during their acute depressive phase. Eighteen of them participated a second time after successful treatment. A group of healthy subjects, matched by age, sex, and smoking behavior, served as a control. Olfactory sensitivity, as measured by threshold tests, was strongly reduced in patients with severe depression. Additional correlative analyses revealed that the lowered sensitivity could partly be predicted by high depression scores. After successful medical treatment, these sensitivity differences were reduced and did not reach the significance level. The subjective odor evaluations (valence and intensity ratings) were not markedly changed in general. The results reveal that olfactory performance in MDD patients is reduced at an early perceptional level of stimulus processing. It is discussed whether this effect can be attributed to the close functional connection between the main olfactory bulb and the amygdala.

Polysomnographic findings in nights preceding a migraine attack.

Sleep recordings were performed in eight patients to analyse sleep alterations preceding migraine attacks. Polysomnographic recordings from nights before an attack were compared with nights without following migraine. We analysed standard sleep parameters and electroencephalogram (EEG) power spectra. The main findings preceding migraine attacks were a significant decrease in the number of arousals, a decrease in rapid eye movement (REM) density, a significant decrease of beta power in the slow wave sleep, and a decrease of alpha power during the first REM period. The results suggest a decrease in cortical activation during sleep preceding migraine attacks. According to the models of sleep regulation, alterations in the function of aminergic or cholinergic brainstem nuclei have to be discussed.

[Biological mechanisms in the psychotherapy of depression]. / Biologische Veränderungen bei der Psychotherapie der Depression.

The question concerning biological changes during psychotherapy can be approached in the context of depressive disorders. In this sphere several clearly defined specific treatments are available with broad evidence for their effectiveness. Furthermore, detailed theories about the biological mechanisms in the context of depression are available. Important impulses for the understanding of the question focussed by this article were initiated by the research on placebos. Based on the evidence supplied by this research, the question can be discussed whether psychotherapy should be considered as a trigger for the self-healing tendencies of an organism.

The calcium response of human T lymphocytes is decreased in aging but increased in Alzheimer's dementia.

BACKGROUND: A significant increase in the [Ca2+]i response of single T lymphocytes to mitogenic stimulation with phytohemagglutinin is reported for 27 Alzheimer patients compared with 27 healthy gender- and age-matched control subjects, regardless of gender. METHODS: The [Ca2+]i signals of T lymphocytes were assessed using the Fura-2-AM method. RESULTS: In Alzheimer's disease (AD) the reaction pattern is similar to that seen in a group of 27 young healthy control subjects who exhibited a marked [Ca2+]i rise after stimulation. During normal aging the reaction pattern of T cells is significantly attenuated in comparison to that found in young subjects. In healthy control subjects differences in age-related changes in calcium homeostasis are highly significant among women, young women showing the most intense cell response. CONCLUSIONS: The elevation of [Ca2+]i appears to be a prerequisite for apoptosis, which is suggested to be involved in the neuronal death occurring in AD. An increased [Ca2+]i in AD is consistent with processes leading to neurodegeneration in AD.

Altered Ca(2+)-homeostasis in single T-lymphocytes of depressed patients.

After stimulation of T-lymphocytes from healthy volunteers with the mitogen phytohemagglutinin (PHA) 40% of the cells exhibit an oscillatory increase in intracellular calcium concentration ([Ca2+]i). During depression the number of cells responding to PHA is reduced to 20%. These cells show a marked decrease in [Ca2+]i-reaction to stimulation and flattened oscillations. This reduction of mitogen-induced Ca2+ signals in T-cells of depressed patients appears to be a reliable state marker in depressive illness and is reversed upon successful treatment with interpersonal psychotherapy (IPT).

K+ currents of human T-lymphocytes are unaffected by Alzheimer's disease and amyloid beta protein.

Alterations of Ca2+ homeostasis have been reported for both fibroblasts and T-lymphocytes of patients with Alzheimer's disease (AD). Considering the importance of K+ conductances for the cellular Ca2+ regulation and the recently reported absence of a K+ channel in Alzheimer fibroblasts, we investigated K+ currents in T-lymphocytes of patients with AD. In addition, the finding that amyloid beta protein affects the Ca2+ signal of T-lymphocytes and the function of K+ channels in fibroblasts prompted us to study a possible influence of amyloid beta protein fragments on K+ channels of T-lymphocytes. Our data, obtained by means of the whole-cell patch-clamp configuration on freshly isolated T-lymphocytes, indicate that K+ channels of these cells do not present any functional deficit in AD, and amyloid beta protein does not mediate an alteration of their currents.

Mitogen stimulated rise of intracellular calcium concentration in single T lymphocytes from patients with major depression is reduced.

1. The authors investigated the signal transduction in T-lymphocytes as a peripheral model for central neurons. 2. Intracellular free calcium concentration [Ca2+]i was measured using fura 2 in T-lymphocytes from 6 patients with major depression during and after depression and from 6 healthy controls. Patients were treated with interpersonal therapy (IPT) but not with psychotropic medication. 3. Phytohemagglutinin (PHA) triggers an oscillatory [Ca2+]i signal in human T-lymphocytes. This implies two mechanisms for [Ca2+]i regulation: inositol phophate (IP) mediated release from intracellular stores and [Ca2+]i influx from the extracellular medium. 4. PHA stimulates 49% of T cells from controls but only 17% of T cells from depressed patients. This finding explains previous results from cells in suspension indicating that [Ca2+]i signals after PHA-stimulation are reduced in cells from depressed patients. 5. Cells from depressed patients show less [Ca2+]i oscillations. Normal oscillation patterns are restored after clinical recovery from depression. 6. Thus altered [Ca2+]i oscillations in T-lymphocytes are a state phenomenon and may give us clues where to search for altered cellular mechanisms during depression.

Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep.

Evidence from animal experiments has suggested that the triggering and maintenance of rapid eye movement (REM) sleep is mainly under the control of cholinergic neurons in the brain stem. Correspondingly, studies in humans have demonstrated that the application of cholinergic agonists or cholinesterase inhibitors provokes an earlier onset of REM sleep. The present study investigated the influence of galanthamine hydrobromide, a reversible cholinesterase inhibitor, on REM sleep regulation in 18 healthy volunteers. After an adaptation night, the subjects were given two doses of galanthamine (10 mg and 15 mg) or placebo at 10 p.m. in a randomized double-blind design. Both doses of galanthamine shortened REM latency (with statistical significance depending on the definition of REM latency used), increased REM density, and reduced slow wave sleep mainly in the first non-REM cycle. Higher doses of galanthamine (15 mg) seem to be accompanied by unwanted side effects that warrant the application of a peripheral antidote. These results are comparable to those for other cholinomimetics and stress the usefulness of galanthamine for pharmacological challenge studies in healthy subjects and depressed patients.

Functional properties of the brain during sleep under subchronic zopiclone administration in man.

Zopiclone, a non-benzodiazepine, has been shown to be efficient in the treatment of transient, short-term or chronic sleep disorders. Apart from its hypnotic effects zopiclone has anxiolytic, anticonvulsant and myorelaxant properties and is therefore hardly distinguishable from benzodiazepines. Dependence liability and discontinuation effects have been reported to be less pronounced. Therefore zopiclone seems to be a hypnotic drug which may cause fewer side effects than conventional benzodiazepines. From the electrophysiological point of view one requires from a hypnotic drug the induction of a physiological sleep pattern as well as no alterations of information processing by the brain. The aim of the present study was to investigate the subchronic effect of zopiclone medication on some functional properties of the sleep EEG in healthy subjects. In order to get better insight into the principles of information processing by the brain during sleep and its alterations under the influence of zopiclone we applied some tools from linear system theory to sleep EEG data. For this purpose we investigated late components of auditory and visual evoked potentials during different sleep stages and calculated from these the so-called amplitude-frequency characteristic of the brain. This function describes the relationship between an input and the output of the investigated system. The main advantage of this kind of analysis is that it enables one to detect functional differences during sleep stages. This information can hardly be obtained from conventional spectral analysis. As a result we could demonstrate that under subchronic zopiclone medication no quantitative or qualitative alterations of the functional sleep EEG properties concerning the transfer properties of the brain under auditory and visual stimulation were detectable.

Cytosolic free [Ca2+] in single T-lymphocytes from depressed patients and healthy controls.

Human lymphocytes are widely used as peripheral models for central neurones. Alterations in immune function have been reported in depressed patients, e.g. mitogen-induced proliferation is impaired during depression. One possible causative mechanism could be altered [Ca2+]i regulation. Phytohaemagglutinin (PHA)-induced rise of [Ca2+]i has been found to be diminished in lymphocyte suspensions from depressed patients (Ecker et al., this issue). We measured PHA-induced rise of [Ca2+]i in single Fura-2 AM-loaded T11+ lymphocytes of patients with major depression and controls to further analyse [Ca2+]i regulation in depression. The [Ca2+]i of resting lymphocytes was 57 +/- 2 nmol/l (mean +/- SEM). There was no difference in resting [Ca2+]i of resting lymphocytes of patients and controls. PHA evoked an increase of [Ca2+]i an 7 out of 14 cells from control subjects up to 400-500 nmol/l. In contrast, only 4 out of 13 cells from depressed patients showed an increase of [Ca2+]i up to 200 nmol/l. In a small fraction of cells from both groups the [Ca2+]i signal is oscillating. Our preliminary data confirm alteration of [Ca2+]i regulation in lymphocytes of depressed patients.

The influence of lorazepam medication upon the transfer properties of the brain during sleep in man.

In order to get better insight into the principles of information processing by the brain during sleep and its alterations under the influence of drugs we applied some tools from linear system theory to sleep EEG data. We investigated late components of auditory and visually evoked potentials (AEPs and VEPs) during different sleep stages and calculated from these the so-called amplitude-frequency characteristics (AFC). The main advantage of this analysis is that it enables one to detect functional differences during different sleep stages. This information can hardly be obtained by conventional spectral analysis. The result of our investigation was that the transfer properties of the brain during sleep were extremely different and that lorazepam medication not only resulted in quantitative alterations of the sleep profile but mainly in highly significant alterations of the functional properties of sleep.

Estimation of the dimensionality of sleep-EEG data in schizophrenics.

Deterministic chaos could be regarded as a healthy flexibility of the human brain necessary for correct neuronal operations. Several investigations have demonstrated that in healthy subjects the dimensionality of REM sleep is much higher than that of slow wave sleep (SWS). We investigated the sleep-EEG of schizophrenic patients with methods from nonlinear system theory in order to estimate the dynamic properties of CNS. We hypothesized that schizophrenics would reveal alterations of their dynamic EEG features indicating impaired information processing. In 11 schizophrenic patients, the EEG's dimensionality during sleep stages II and REM was reduced. We suggest that such lower dimensional chaotic processes might be associated with an overloading of neuronal networks during sleep and therefore the psychopathology of schizophrenics might be due to impaired complexity of their EEG's dynamics.